Diagnostic and confirmative procedures require fulfillment of three conditions for termination of pregnancy due to congenital abnormalities: (1) the diagnosis should be confirmed by at least three experts with expertise in the related field; (2) the prenatal diagnosis and termination should be done before day 120 of conception or before the 134th day from the last menstrual period (~17 weeks); and (3) the request for prenatal diagnosis and termination must come from both parents. Specimen sampling for prenatal genetic diagnosis can be performed at 9-11 weeks of gestation from chorionic villi25
; or at 10-12 weeks, from amniotic fluid10
; so that the time period is sufficient to allow a complete diagnostic procedure.
We propose a diagnostic pathway to assist clinicians in deciding on the appropriateness of termination of pregnancy once a fetus is found to carry the SMN1 deletion. This decision-making process takes into account the copy number variation of the disease-modifying genes, which will make prediction of severity accurate, allowing termination of pregnancy within the time period permissible by jurists in the Muslim community (). outlines the flow of the diagnostic pathway we propose for determining the severity of SMA. When both parents request a prenatal genetic diagnosis, it is important to make sure that the index case is clinically SMA type 1 with deletion of the SMN1 gene. It is also crucial to initially determine that the gestational age is younger than 120 days and that the time period is enough to allow complete diagnostic procedure.
Flowchart describing the pathway of prenatal diagnostic procedures in determining SMA diagnosis and severity.
Following fetal specimen sampling and subsequent DNA extraction, the SMN1 deletion test is performed on the fetal DNA. Microsatellite marker analysis is performed to rule out the possibility of contamination with a maternal specimen. This is especially important in the case when no SMN1 deletion is proven. In this case, clinical reassessment is suggested if there is no indication of maternal contamination. Re-sampling of fetal specimen is required if there is an indication of maternal contamination. If SMN1 deletion is proven, the test would go further, into SMN2 copy number analysis. A single copy of SMN2 directly determines that the fetus will have a type 1 clinical severity of SMA. More than two copies of SMN2 disable severity determination. Two copies of SMN2 require NAIP deletion analysis, whereby only if the gene is deleted, can SMA type 1 be determined. Therefore, SMA type 1 can be determined based on only two genotypes (SMN1-SMN2-NAIP): 0-1 or 0-2-0. The diagnosis of SMA type 1 should be decided by consensus among a panel of at least three experts. Finally, termination of pregnancy should be based on a request from both parents after the final decision is made, provided the gestational age is still under 120 days.
The above diagnostic pathway should, however, be interpreted with caution in fetuses with deletion of only SMN1
exon 8, when the SMN1
exon 7 is found intact. This caution is of importance since only a genetic alteration within exon 7 has been proven to cause SMA.28
Previous studies have shown variable severity among individuals with more than one SMN2
copies and non-deletion of NAIP
. It is therefore not recommended to determine the severity if the fetus has a genotypic pattern other than those described within